Structure-Based Design, Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors
Abstract
:1. Introduction
2. Results and Discussion
2.1. Analysis of Spindlin1-A366 Complex
2.2. Docking Studies
2.3. Molecular Dynamic Simulations
2.4. Re-Scoring Using Prime MM-GBSA
2.5. Structure–Activity Relationships
2.6. Synthesis
3. Materials and Methods
3.1. Synthesis
3.1.1. General Methods and Materials
3.1.2. Synthesis and Analytical Data
3.2. Biological Assays
3.2.1. Fluorescence Polarization Assay
3.2.2. Reagents for Histone Methyltransferase Assays
3.2.3. Expression and Purification of G9a and GLP and SAHH
3.2.4. Coupled Enzyme Fluorescent Histone Methyltransferase Assay
3.3. Computational Studies
3.3.1. Docking Studies
3.3.2. Molecular Dynamic Simulations
3.3.3. Prime MM-GBSA
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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| |||||||
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Compounds | R1 | R2 | R3 | R4 | Spin1 IC50 ± SD (nM) [a] | G9a IC50 (nM) [b] | GLP IC50 (nM) [b] |
A366 | Me | H | | | 182.6 ± 9.1 [31] | 38 [c] | 51 |
1a | Et | OEt | | | 70% @ 25 μM [d] | ||
1b | Me | H | | | 81% @ 100 μM [d] | ||
1c | Me | H | | | 42% @ 50 μM [d] | >20,000 | >20,000 |
1d | Me | H | | | Inactive | ||
1e | Me | H | | | Inactive | ||
1f | Me | H | | | 169 ± 13 | 431 | 334 |
1g | Et | H | | | 316 ± 26 | 243 | 2969 |
1h | Me | CN | | | 3900 ± 700 | ||
1i | Me | Cl | | | 1600 ± 200 | >20,000 | >20,000 |
1j | Me | OMe | | | 2500 ± 200 | ||
1k | Me | Ac | | | 11,800 ± 210 | ||
1l | Et | H | | | 567 ± 35 | ||
1m | 2-Pr | H | | | 3300 ± 470 | ||
1n | Me | H | | | 255 ± 35 | 779 | 527 |
1o | Me | H | | | 1210 ± 90 | >20,000 | >20,000 |
1p | Me | H | | | 157 ± 12 | 759 | 470 |
1q | Me | H | | | (R): 470 ± 27 (S): 478 ± 34 (rac): 584 ± 31 | (rac): 2321 | (rac): 4432 |
1r | Me | H | | | 408 ± 35 | 3191 | 3185 |
1s | Me | H | | | 360 ± 20 | >20,000 | >20,000 |
1t | Me | H | | | 467 ± 15 | >20,000 | >20,000 |
1u | Me | H | | | 1250 ± 50 | >20,000 | >20,000 |
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Luise, C.; Robaa, D.; Regenass, P.; Maurer, D.; Ostrovskyi, D.; Seifert, L.; Bacher, J.; Burgahn, T.; Wagner, T.; Seitz, J.; et al. Structure-Based Design, Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors. Int. J. Mol. Sci. 2021, 22, 5910. https://doi.org/10.3390/ijms22115910
Luise C, Robaa D, Regenass P, Maurer D, Ostrovskyi D, Seifert L, Bacher J, Burgahn T, Wagner T, Seitz J, et al. Structure-Based Design, Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors. International Journal of Molecular Sciences. 2021; 22(11):5910. https://doi.org/10.3390/ijms22115910
Chicago/Turabian StyleLuise, Chiara, Dina Robaa, Pierre Regenass, David Maurer, Dmytro Ostrovskyi, Ludwig Seifert, Johannes Bacher, Teresa Burgahn, Tobias Wagner, Johannes Seitz, and et al. 2021. "Structure-Based Design, Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors" International Journal of Molecular Sciences 22, no. 11: 5910. https://doi.org/10.3390/ijms22115910